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J Chem Theory Comput. 2010 Nov 9;6(11):3427-3441.

Computing Relative Free Energies of Solvation using Single Reference Thermodynamic Integration Augmented with Hamiltonian Replica Exchange.

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1
Biotechnology HPC Software Applications Institute, Telemedicine and Advanced Technology Research Center, US Army Medical Research and Materiel Command, Fort Detrick, MD 21702.

Abstract

This paper introduces an efficient single-topology variant of Thermodynamic Integration (TI) for computing relative transformation free energies in a series of molecules with respect to a single reference state. The presented TI variant that we refer to as Single-Reference TI (SR-TI) combines well-established molecular simulation methodologies into a practical computational tool. Augmented with Hamiltonian Replica Exchange (HREX), the SR-TI variant can deliver enhanced sampling in select degrees of freedom. The utility of the SR-TI variant is demonstrated in calculations of relative solvation free energies for a series of benzene derivatives with increasing complexity. Noteworthy, the SR-TI variant with the HREX option provides converged results in a challenging case of an amide molecule with a high (13-15 kcal/mol) barrier for internal cis/trans interconversion using simulation times of only 1 to 4 ns.

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